Process for the preparation of 7-substituted 3-alkyl-3h-isobenzofuran-1-one derivatives

ABSTRACT

The present invention relates to a first compound having the formula  
                 
 
wherein R is halogen, R 1 S(O) n  or (R 1 ) 2 NC(X)O; R 1  is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, aryl-C 1 -C 8 -alkyl or aryl; n is 0, 1, 2 or 3; X is O or S; and R 3  is C 2 -C 5 alkyl or C 1 -C 5 haloalkyl, or a salt thereof. The present invention is also directed to a second compound having the formula  
                 
 
wherein R is fluorine, bromine, iodine, R 1 S(O) n  or (R 1 ) 2 NC(X)O; R 1  is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, aryl-C 1 -C 8 alkyl or aryl; n is 0, 1, 2 or 3; X is O or S; and R 2  is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, with the proviso that R 1  is different from C 1 -C 8  alkyl or aryl if X is S, R is different from iodine if R 2  is methyl, and R is different from fluorine, bromine or iodine if R 2  is hydrogen.

This application is a continuation of application Ser. No. 10/478,020filed Apr. 7, 2004, still pending, which is the National Stage ofInternational Application No. PCT/EP02/05572, filed May 21, 2002, whichclaims the benefit of Swiss Application No. 954/01, filed May 22, 2001.

The present invention relates to a novel process for the preparation of7-substituted 3-alkyl-3H-isobenzofuran-1-one derivatives, to their useas intermediates in the preparation of byproduct-free7-thio-3H-isobenzofuran-1-one derivatives, and to their use asintermediates in the preparation of herbicidal7-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methyl-3H-isobenzo-furan-1-one.

WO 91/05781 describes a process for the preparation of7-thio-3-methyl-3H-isobenzofuran-1-one. According to that process, thatcompound is obtained by rearrangement in three steps starting from7-hydroxy-3-methyl-3H-isobenzofuran-1-one according to Kwart-Newmann viathe 7-(N,N-dimethylthiocarbamoyl)oxy-3-methyl-3H-isobenzofuran-1-onederivative with heating at about 170-200° C. to the7-(N,N-dimethylcarbamoyl)thio-3-methyl-3H-isobenzofuran-1-oneintermediate and is then subjected to alkaline hydrolysis. Since thestarting material 7-hydroxy-3-methyl-3H-isobenzofuran-1-one also has tobe prepared by a multistep process, that process for the preparation of7-thio-3-methyl-3H-isobenzofuran-1-one is troublesome and unsuitable forcommercial synthesis.

In a further process, starting from 3-nitrophthalic acid the targetcompound 7-thio-3-methyl-3H-isobenzofuran-1-one is obtained in fourreaction steps in a yield of about 60%.

The latter reaction sequence consists of introducing a methyl groupusing methylmagnesium bromide or malonic acid, reducing a nitro groupand a carbonyl group, and then diazotising the resulting7-amino-3-methyl-3H-isobenzofuran-1-one in the presence of sodiumhydrogen sulfide.

Pest Manag Sci. 57, 205-224 (2001) describes further synthesis processesfor the preparation of 7-thio-3-methyl-3H-isobenzofuran-1-one (compoundof formula Xc in Figure 7 on page 211) in which undesired disulfidebyproducts (compounds of formula Xc′ in Figure 7) are substantiallyexcluded, e.g. by reduction and simultaneous ring-closure of2-acetyl-6-nitrobenzoic acid with Raney nickel, diazotisation of the7-amino-3-methylphthalide (compound of formula XXa) obtained in a crudeyield of 89.8%, and subsequent thiol formation by treatment of thecorresponding diazonium salt with an alkaline potassium xanthogenatesolution in a crude yield of 87.5% over the last two reaction steps.

That process too is unsatisfactory in terms of volumetric and chemicalyields. In addition, the use of xanthogenates as source of sulfur forthe thiol formation gives rise to volatile, unpleasant-smelling, toxic,sulfur-containing waste products, such as e.g. COS, CS₂ and H₂S.Moreover, individual reaction steps, such as e.g. the reduction of3-nitrophthalic acid derivatives to the corresponding amines (formationof hydroxylamine byproducts), have a significant thermal safety risk(TMR (=‘time to maximum rate’)<2 hours). From the standpoint ofindustrial-scale preparation processes, these aspects are problematicespecially in ecological terms and in respect of process safety.

Monatsh. Chem. 123(12), 1125-1134 (1992) describes the preparation of7-chlorophthalides methyl- or phenyl-substituted in the 3-position byortho-lithiation of 3-chlorobenzanilides with n-butyllithium, reactionwith electrophiles e.g. acetaldehyde, for the preparation of7-chloro-3-methyl-phthalides, and subsequent acid-catalysed cyclisation.As described above in Pest Manag Sci. 57, 205-224, such7-chloro-3H-isobenzofuran-1-ones can be converted by treatment with anexcess of alkylmercaptides, e.g. sodium methyl- or ethyl-mercaptide, attemperatures of about 100-130° C. in N,N-dimethylformamide to thedesired 7-mercapto-3H-isobenzofuran-1-ones by way of a7-alkylmercapto-3H-isobenzofuran-1-one intermediate. That process too isunsuitable for industrial-scale processes because of the yield, processsafety and the formation of unpleasant-smelling dialkylsulfides and isalso uneconomical owing to the cost of the reagent n-butyllithium.

Tetrahedron Lett. 36(39), 7089-7092 (1995) and J. Chem. Soc., PerkinTrans. I, 1997, 787-793 describe the oxidative, free-radical-forming,photochemical preparation of lactones at room temperature starting fromo-alkyl aromatic carboxylic acids in the presence of[bis(tri-fluoroacetoxy)iodo]benzene and iodine (phenyl-I(O(O)CCF₃)₂/I₂)by way of a hypoiodite species in an organic solvent, such asdichloromethane, and irradiation with a high-pressure mercury vapourlamp in moderate to good yields (from 5 to 90%, based on the startingcompound) of the desired lactone, and Tetrahedron Asym. 8, 3765-3774(1997) describes the preparation of 3-alkylphthalide derivativesstarting from o-alkyl aromatic carboxylic acids as biocatalysed benzylicoxidation and lactonisation using microorganisms, such as e.g.Pseudomonas putida. Neither synthesis process can be carried out on anindustrial scale.

Chem. Ber. 38, 3981-3985 (1905) describes a synthesis variant for thepreparation of phthalide derivatives starting from aromaticortho-aldehydro acids by means of nucleophilic addition using Grignardreagents with the formation of the corresponding alcohol derivatives andsubsequent lactonisation of the same.

J. Org. Chem. 51, 3849-3858 (1986) and J. Organomet. Chem. 231, 79-90(1982) describe a further synthesis variant for 3-methylphthalides bythe reduction and lactonisation of 2-methylketonecarboxylic acids usingsodium borohydride and ruthenium-triphenyl-phosphine complex andhydrogen (RuCl₂(PPh₃)₃/H₂), respectively, in a quantitative yield, and ayield of 51%, respectively.

Tetrahedron Lett. 28(43), 5175-5176 (1987), J. Chem. Soc. Perkin TransII, 1983, 595-601, Ind. J. Chem. Sect. B 24, 1202-1203 (1985) and Bull.Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.) 31(10), 2041-2046 (1982)describe the preparation of γ- and δ-lactones from alkanecarboxylicacids by oxidation with oxygen-containing compounds, such as e.g.2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or sodium persulfate(Na₂S₂O₈), in the presence of catalytic amounts of copper(II) chlorideor nickel(II) chloride, or cerium(IV) ammonium nitrate(Ce(NH₄)₂(NO₃)₆/HNO₃) in a yield of 10-35%.

Tetrahedron Lett. 29(1), 85-88 (1988) describes the preparation ofγ-lactones from γ-arylbutyric acids via halogenation with bromine in thepresence of the free-radical initiator α,α′-azoisobutyronitrile incarbon tetrachloride in a yield of 53%.

J. Org. Chem. 45, 2365-2368 (1980) describes the palladium(0)-catalysedcarbonylation of isolated methyl-, methoxy-, halo- and nitro-substitutedarenediazonium tetrafluoroborates in acetonitrile in the presence ofsodium acetate and carbon monoxide in yields of from 28 to 86%, and J.Chem. Soc., Perkin Trans. I, 1998, 407-410 describes thepalladium(II)-catalysed carbonylation of isolated bisarenediazoniumtetrafluoroborate salts in methanol at room temperature and normalpressure in yields of from 76 to 93%, based on the diazonium salt.

WO 96/19443 discloses a process for the preparation of aromatico-sulfo-carboxylic acids by means of diazotisation of the correspondinganiline-2-sulfonic acids and subsequent palladium(II)-catalysedcarbonylation of the diazonium salt formed, with or without isolation ofthat diazonium salt.

Whilst the preparation of sulfides by the reaction of halides withmercaptides, xanthates, thiourea, alkali metal sulfides or alkali metaldisulfides (the latter being prepared in situ from alkali metal sulfidesand sulfur) are well-documented standard processes, as described e.g. inJ. Org. Chem. 56, 3728-3729 (1991), J. Am. Chem. Soc. 68, 498 (1946),Gazz. Chim. Ital. 110, 301-303 (1980), Org. Synth., Coll. Vol. III,86-87 and Chem. Pharm. Bull. 33, 5184-5189 (1985), they are allunsuitable for industrial-scale batches, because:

a) the reagents used are too expensive, such as e.g. the use of sodiumborohydride for the reductive working-up of disulfide derivatives,

b) the resulting product yields and product purities are unsatisfactoryfor industrial-scale preparation processes,

c) the amount of di- and poly-sulfides formed is too great, and

d) the reproducibility cannot be guaranteed.

The problem of the present invention is to overcome those disadvantagesand provide a technically simpler process suitable for industrial-scaleprocesses that is associated with little outlay in terms of apparatus.

It has now been found, surprisingly, that 3-alkyl-3H-isobenzofuran-1-onederivatives substituted specifically in the 7-position can readily beprepared with high product yield, product purity and selectivity, in aneconomically and ecologically especially advantageous manner, avoidingthe disadvantages of the processes described above, from inexpensive andreadily accessible starting compounds, such as e.g. aniline derivatives,using technically simple, reproducible and safe process conditions byway of only three or four reaction steps, by diazotising2,6-disubstituted aniline derivatives, carbonylating the resultingdiazonium salt in the presence of catalysts and cyclising the resultingbenzoic acid derivative in the presence of a halogenating agent and afree-radical initiator to form the corresponding lactone derivative.That lactone derivative is then used in a further, fourth reaction stepfor a nucleophilic aromatic substitution reaction with sulfides and asubsequent, specific purification step at a controlled pH range for thepreparation of byproduct-free 7-thio-3H-isobenzofuran-1-one, which canbe used directly e.g. for the preparation of herbicides according toEP-B-0 447 506. In that process, careful attention is given to thecritical factors and crucial reaction parameters in all the reactionsteps including working-up, such as e.g. the choice of solvents, acids,bases and buffer systems, the water content in the reaction mixture, thepH range, the reaction temperature, the charging procedure for thepalladium complex, pressure and reaction time.

The present invention accordingly relates to a process for thepreparation of 7-substituted 3-alkyl-3H-isobenzofuran-1-ones of formulaI

whereinR is halogen, R₁O, R₁S(O)_(n) or (R₁)₂NC(X)O;R₁ is C₁-C₈alkyl, aryl-C₁-C₈alkyl, C₁-C₈haloalkyl or aryl;n is 0, 1, 2 or 3;X is O or S; andR₂ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, in which process, in asolvent,(1) an aniline derivative of formula IV

whereinR is as defined above, and R₃ is C₁-C₅alkyl or C₁-C₅haloalkyl,is diazotised in the presence of a mineral acid to form thecorresponding diazonium salt of formula II

whereinR and R₃ are as defined above, A^(m−) is an anion such as e.g. PF₆ ⁻,BF₄ ⁻, HSO₄ ⁻, SO₄ ²⁻, CH₃(C₆H₄)SO₃ ⁻, CH₃SO₃ ⁻ or (Zn(II)Cl₃)⁻, and mis 1 or 2,(2) the resulting diazonium salt of formula II is carbonylated in thepresence of a catalyst, CO and optionally a buffer, to form a benzoicacid derivative of formula III

whereinR and R₃ are as defined above, and(3) the benzoic acid derivative of formula III is then subjected tobenzylic lactonisation in the ortho-position alkyl chain R₃ in thepresence of a free-radical initiator and a halogenating agent.

The compounds of formula I prepared according to the invention are usedas starting compounds in the preparation of compounds of formula Ia

wherein R₂ is as defined for formula I, by reacting a compound offormula I

wherein R is halogen, R₁SO₂ or (R₁)₂NC(X)O; and X, R₁ and R₂ are asdefined for formula I, with the reagent of formula XM₂S_(q)  (X),wherein M is an alkali metal or hydrogen, and q is 1, 2 or a fractionalnumber from 1 to 7, with the proviso that at least one M is an alkalimetal (halogen-sulfide exchange; Reaction scheme 3).

The compounds of formulae I and Ia may be in the form of optical isomersand mixtures of isomers depending on the substituents R/R₁ and/or R₂.Unless enantiomerically pure starting materials are used, the compoundsof formulae I and Ia in the processes described above are generallyobtained in the form of racemates or diastereoisomeric mixtures, whichcan optionally be separated on the basis of physicochemical propertiesaccording to known methods, such as e.g. fractional crystallisationafter salt formation with optically pure bases or metal complexes or bychromatographic processes, such as e.g. high pressure liquidchromatography (HPLC) on acetylcellulose.

In the present invention, the compounds of formulae I and Ia are to beunderstood as including both the enriched and optically pure forms ofthe stereoisomers in question and the racemates or diastereoisomers.Where there is no specific reference to the individual opticalantipodes, the racemic mixtures under the given formula are to beunderstood as being those obtained in the preparation process accordingto the invention.

The present invention includes also the salts that can be formed by thecompounds of formulae Ia and III.

For example, owing to their acidity, compounds of formulae Ia and IIIcan readily be converted in the presence of bases (proton acceptors)into the corresponding salts (e.g. with metal ions or ammonium cations).Any customary proton acceptor can be used as base. Such salts are, forexample, alkali metal salts, such as e.g. sodium and potassium salts;alkaline earth metal salts, such as e.g. calcium and magnesium salts;ammonium salts, that is to say unsubstituted ammonium salts and mono- orpoly-substituted ammonium salts, such as e.g. triethylammonium andmethylammonium salts, or salts with other organic bases or othercations, such as e.g. sulfonium or phosphonium cations. Sulfoniumcations are, for example, tri(C₁-C₄alkyl)sulfonium cations, which can beobtained from the corresponding alkali metal salts e.g. by conversioninto different salts using, for example, a cation exchanger.

Of the alkali metal hydroxides and alkaline earth metal hydroxides assalt formers, special mention may be made, for example, of thehydroxides of lithium, sodium, potassium, magnesium and calcium, butespecially those of sodium and potassium. Suitable ammonium salt formersare described, for example, in WO 97/41112.

Examples of amines suitable for ammonium salt formation that come intoconsideration are ammonia and also primary, secondary and tertiaryC₁-C₁₈alkylamines, and heterocyclic amines. Especially suitable are, forexample, trimethylamine, triethylamine, tri-n-propylamine,triisopropylamine, triisobutylamine, pyridine, 5-ethyl-2-methylpyridineand morpholine. More especially suitable are trimethylamine andtriethylamine.

In the above definitions, halogen is to be understood as being fluorine,chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

The alkyl groups appearing in the substituent definitions are, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl and tert-butyl, and also the pentyl, hexyl, heptyl and octylisomers.

Haloalkyl groups preferably have a chain length of from 1 to 6 carbonatoms. Haloalkyl is, for example, fluoromethyl, difluoromethyl,difluorochloromethyl, trifluoromethyl, chloromethyl, dichloromethyl,dichlorofluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl,2,2,2-trichloroethyl or pentafluoroethyl, preferably trichloromethyl,difluoromethyl, difluorochloromethyl, trifluoromethyl ordichlorofluoromethyl.

Aryl in the definition of the radical R₁ is α- or β-naphthyl, especiallyphenyl, it being possible for those aromatic rings to carry one or moreidentical or different substituents, such as e.g. halogen, nitro, cyano,C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkyl and C₁-C₄haloalkyl. The sameapplies also to arylalkyl in the definition of the radical R₁.

Corresponding meanings can be assigned also to the substituents incomposite definitions of R, such as e.g. alkoxy, haloalkoxy, arylalkyl,aryloxy, arylthio, arylsulfonyl, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylsulfonyloxy, haloalkylthio, haloalkylsulfinyl,haloalkylsulfonyl, haloalkylsulfonyloxy, arylalkylthio,arylalkylsulfinyl and arylalkylsulfonyl.

A^(m−) in the diazonium salt of formula II denotes a mono- (m=1) ordi-valent (m=2) anion and according to the definition includes e.g. PF₆⁻, BF₄ ⁻, HSO₄ ⁻, SO₄ ²⁻, CH₃(C₆H₄)SO₃ ⁻, CH₃SO₃ ⁻ and (Zn(II)Cl₃)⁻,preferably PF₆ ⁻ and BF₄ ⁻.

The reagent of formula X, M₂S_(q), is, when both M are alkali metals andq is 1, an alkali metal sulfide, such as e.g. sodium sulfide (Na₂S),potassium sulfide (K₂S), lithium sulfide (Li₂S) or sodium potassiumsulfide (NaKS); when one M is an alkali metal and the second M ishydrogen and q is 1, the reagent of formula X is an alkali metalhydrosulfide, such as e.g. sodium hydrosulfide (NaHS) or potassiumhydrosulfide (KHS); when both M are alkali metals and q is 2, thereagent of formula X is an alkali metal disulfide, such as e.g. sodiumdisulfide (Na₂S₂), potassium disulfide (K₂S₂) or sodium potassiumdisulfide (NaKS₂), and finally when one M is an alkali metal and thesecond M is hydrogen and q is 2, the reagent of formula X is an alkalimetal hydrodisulfide, such as e.g. sodium hydrodisulfide (NaHS₂) orpotassium hydrodisulfide (KHS₂). For higher values of q, the reagentM₂S_(q) of formula X denotes compounds such as, for example, Na₂S₄ ormixtures prepared in situ from lower alkali metal sulfides and sulfur.The definition of M₂S_(q) also includes mixtures of lower and higheralkali metal sulfides. The nucleophilic species are then e.g. NaS⁻, HS⁻,NaS₂ ⁻ and HS₂ ⁻.

The process according to the invention is especially suitable for thepreparation of compounds of formula I wherein R is chlorine or bromine,especially chlorine.

The process according to the invention is also especially suitable forthe preparation of compounds of formula I wherein R₂ is CH₃.

The process according to the invention is also especially suitable forthe preparation of compounds of formula I wherein R is chlorine and R₂is CH₃.

The preparation of compounds of formula I by way of three reaction steps(Steps (1), (2) and (3)) and the use thereof in a derivatisation step bymeans of a nucleophilic aromatic substitution reaction with the reagentof formula X M₂S_(q) (X) (reaction step 4, halogen-sulfide exchange) toform compounds of formula Ia will be explained in greater detail in thefollowing Reaction schemes 1, 2 and 3.

In the first Step (1) in Reaction scheme 1, the diazotisation of theaniline derivative of formula IV is carried out advantageously in asolvent and in the presence of a 20 to 120% excess of a mineral acid,based on the diazotisation reagent, at reaction temperatures in therange of from −5° to 25° C.

As diazotisation reagent there may be used the customary nitrites, suchas, for example, alkali metal nitrites, dinitrogen trioxide (N₂O₃) ororganic nitrites, preferably sodium nitrite, potassium nitrite, N₂O₃,tert-butyl nitrite or pentyl nitrite in equivalent amounts or in aslight excess of from 3 to 10% molar equivalents, based on the anilinederivative of formula IV.

Suitable solvents for the diazotisation in Step (1) are C₁-C₄-carboxylicacids, nitriles, ethers, amides, carbonates, alcohols or water, ormixtures thereof, for example acetic acid, propionic acid, acetonitrile,tetrahydrofuran, dioxane, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), 1-methyl-2-pyrrolidone (NMP),1,3-dimethyl-2-imidazolidinone (DMI), propylene carbonate, isoamylalcohol, n-pentanol, isopropanol, n-propanol, tert-butanol, n-butanol,ethanol, methanol or water, or mixtures thereof. Preference is given toacetic acid, acetonitrile, alcohols and water.

Suitable mineral acids for the diazotisation reaction in Step (1) arepreferably sulfuric acid, hydrochloric acid, nitric acid and hydrobromicacid.

The catalysts that come into consideration for the carbonylation of thediazonium salts of formula II in Step (2) (Matsuda carbonylation,Reaction scheme 1) are generally palladium(II) and palladium(0)complexes. Examples of such palladium complexes are palladium(II)dihalides, palladium(II) acetate, palladium(II) sulfate, palladium(II)acetylacetonate, bis-hydridopalladium(II) tetrahalides (H₂PdCl₄),bis(alkali metal)palladium(II) tetrahalides,cis,cis-1,5-cyclooctadiene-palladium(II) dihalides, bis(acetonitrile)-and bis(benzonitrile)-palladium(II) dihalides,bis(dibenzylideneacetone)palladium(0) (Pd₂(dba)₃), [Pd(η₃-C₃H₅)Cl]₂,[Pd(η₃-Me-C₃H₄)Cl]₂, [Pd(η₃-C₃H₅)(acac)]₂,bis(triphenylphosphine)palladium(II) dihalides andtetrakis(triphenylphosphine)palladium(II) dihalides.

The palladium complexes are prepared ex situ or optionally, in the caseof ligand-carrying complexes, such as e.g.triphenylphosphinepalladium(II) complexes, also in situ.

Examples of preferred palladium(0) and palladium(II) catalysts preparedex situ or in situ are PdCl₂, PdBr₂, H₂PdCl₄ (in the form of a solutionin hydrochloric acid), Na₂[PdCl₄], Li₂[PdCl₄], K₂[PdCl₄], Pd(acac)₂,PdCl₂(COD) (═PdCl₂(cis,cis-1,5-cyclooctadiene)), PdCl₂(AcCN)₂,PdCl₂(PhCN)₂, PdCl₂(PPh₃)₂, PdCl₂(PPh₃)₄ and Pd(PPh₃)₄.

Such palladium complexes are known and have been described many times inthe literature, such as e.g. in J. Am. Chem. Soc. 121, 4369-4378 (1999),EP-A-0 564 406, EP-A-0 646 590 and ‘Palladium Reagents and Catalysts’,Editor J. Tsuji, John Wiley & Sons, 1995.

The palladium catalysts are used in an amount of from 0.1 to 5.0 mol %,preferably from 0.25 to 1.00 mol %, based on the compound of formula II.

Suitable solvents for the carbonylation in Step (2) are the same asthose listed for the diazotisation in Step (1). Generally, directlybefore the carbonylation reaction, from 0 to equivalents of water, basedon the compound of formula IV, are metered in or an excess of water isreduced using carboxylic acid anhydrides, such as e.g. acetic anhydride(Examples P2 and P3).

The palladium-catalysed carbonylation reaction of the diazonium salt offormula II in Step (2) is carried out at a CO pressure of from 1 to 100bar and at reaction temperatures of from −20° to 60° C., preferably in apressurised vessel (autoclave).

The two Steps (1) and (2), the diazotisation and carbonylation inReaction scheme 1, can be carried out, in principle, according to twodifferent variants:a) as a two-step reaction with isolation of the intermediately formed,stable diazonium salt of formula II

wherein R, R₃, A^(m−) and m are as defined for formula I, orb) preferably as a single-step reaction without isolation of theintermediately formed diazonium salt of formula II

wherein R, R₃, A^(m−) and m are as defined for formula I, with theresult that the diazotisation of the aniline derivative of formula IVand the palladium-catalysed carbonylation reaction of the compound offormula II in Steps (1) and (2) are carried out as a continuous process,that is in the same reaction vessel and solvent system as a one-potreaction.

When selecting one of the two variants a) or b), in addition toconsidering the stability of the diazonium salt of formula II, thereactants present in the reaction mixture must also be taken intoaccount and must be matched according to the process variant in questionin order to avoid possible secondary reactions and thus a reduction inyield. Critical factors are, for example, the selection of the solventor solvent mixture, of the nitrite reagent as potential catalyst poisonand of the mineral acid, e.g. sulfuric acid as opposed to hydrochloricacid, and the buffering of excess mineral acid, for example withacetates, the water content in the reaction mixture, and the nature ofthe palladium catalyst and its charging procedure, especially thesequence of the addition of CO and the metering of the palladium complexinto the reaction mixture. In addition, the reaction parameters, such ase.g. the reaction temperature and the CO pressure in the system, may becritical to the manner in which each reaction proceeds.

Accordingly, prior to the catalytic carbonylation of the diazonium saltof formula II in Step (2) the mineral acid in the reaction mixture isadvantageously buffered with a buffer system, preferably using an alkalimetal acetate, for example sodium acetate.

Once the diazotisation is complete, excess nitrite reagent present inthe reaction mixture is destroyed in customary manner known to theperson skilled in the art, for example by adding sulfamic acid (ExamplesP2 and P3) until nitrite is no longer detectable (nitrite detectionusing KI paper moistened with 1N aqueous hydrochloric acid solution) andthe reaction mixture so treated is prepared for the subsequentpalladium-catalysed carbonylation step, which is preferably carried outin the same reaction vessel.

In the case of the two-step variant a), with isolation of the diazoniumsalt of formula II, the following aqueous base systems, for example, aresuitable for the subsequent carbonylation reaction: alkali metal,alkaline earth metal and ammonium salts of acetates, propionates,butyrates, benzoates and stearates, and of carbonates, for examplelithium, sodium, potassium, calcium, barium and ammonium acetate,propionate and benzoate, and lithium, sodium, potassium, calcium,barium, magnesium, ammonium and (C₁-C₁₈alkyl)₃NH salts of carbonates.

In an especially preferred variant of Steps (1) and (2) according to theinvention, the diazotisation of the aniline derivative of formula IV(Step (1)) is carried out using an equivalent amount of sodium nitritein the presence of a 25% excess of sulfuric acid, based on the nitrite,and acetic acid as solvent, and the subsequent palladium-catalysedcarbonylation reaction (Step (2)) is carried out using Pd₂(dba)₃.CHCl₃at a CO pressure of from 2 to 10 bar and a reaction temperature of from20° to 60° C. in the same reaction vessel as a one-pot reaction.

In Step (3) in Reaction scheme 2, the treatment with the halogenatingreagent and subsequent or simultaneous ring-closure reaction(lactonisation) of the benzoic acid derivative of formula III areadvantageously carried out using halogen, preferably chlorine orbromine, using hypohalite, preferably hypochlorite or hypobromite, orusing sulfuryl halide, preferably sulfuryl chloride or sulfuryl bromide,in a solvent, such as e.g. a chlorinated hydrocarbon, a C₁-C₄carboxylicacid or water, or a mixture thereof, and in the presence of afree-radical initiator, such as e.g. α,α′-azoisobutyronitrile or benzoylperoxide.

The halogenating reagent is advantageously used in an amount of from 1to 2 molar equivalents, based on the benzoic acid derivative of formulaIII.

The solvents especially suitable for Step (3) are, for example,chlorinated hydrocarbons, for example tetrachloroethylene, chloroform,dichloromethane, chlorobenzene and dichlorobenzene, carboxylic acids,for example acetic acid or propionic acid, or water, or mixturesthereof, the reaction temperature being from −20° to 160° C. and thereaction pressure being from 1 to 100 bar.

In an especially preferred variant of Step (3) according to theinvention, the treatment with the halogenating reagent and thering-closure reaction of the compound of formula III are carried outwith from 1 to 1.3 molar equivalents of bromine, based on the compoundof formula III, in chlorobenzene at reaction temperatures of from 80° to100° C. and at normal pressure in the presence ofα,α′-azoisobutyronitrile as free-radical initiator.

For good selectivity and in order to carry out the reaction in Step (3)efficiently, the choice of the solvent, the amount of halogenatingreagent and of free-radical initiator and the purity of the startingcompound of formula II, and the reaction parameters, such as temperatureand duration of the reaction, are critical in order as far as possibleto suppress over-oxidation and the formation of halides, such as e.g.phenyl nuclear halides and alkyl halides (R₂). Excess halogenating andoxidising agents can be rendered inactive in the course of a working-upprocess, for example using an alkali metal thiosulfate, for exampleusing sodium thiosulfate (Example P4).

The yields of isolated product of formula I in all three Steps (1), (2)and (3) are generally >70% of theory (depending on the solvent and acidused, the optimum water content, the charging procedure for thepalladium catalyst, the nature and amount of halide and purity of thestarting materials) with the final product having a purity of >90%.

The starting compounds of formula IV in Reaction scheme 1 are known e.g.from DE-A-2 405 479 and Ann. Chem. 424, 255 (1921).

All the reagents used, such as diazotisation agents, palladium(II) andpalladium(0) catalysts, phosphine ligands and free-radical initiators,are also known or can be prepared according to known processes.

The compounds of formula III

wherein R is halogen, R₁S(O)_(n) or (R₁)₂NC(X)O; R₁ is C₁-C₈alkyl,C₁-C₈haloalkyl, aryl-C₁-C₈-alkyl or aryl; n is 0, 1, 2 or 3; X is O orS; and R₃ is C₂-C₅alkyl or C₁-C₅haloalkyl, and salts thereof are novel.They make a significant contribution in structural terms to thepreparation of the lactones of formulae I and Ia and have been developedespecially for the process according to the invention.

Preferred compounds of formula III are those wherein R is halogen orR₁S(O)₂ and R₃ is ethyl.

The compounds of formula I

wherein R is fluorine, bromine, iodine, R₁S(O)_(n) or (R₁)₂NC(X)O; R₁ isC₁-C₈alkyl, C₁-C₈-haloalkyl, aryl-C₁-C₈alkyl or aryl; n is 0, 1, 2 or 3;X is O or S; and R₂ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, are alsonovel. They make a substantial contribution in structural terms to thepreparation of the lactones of formula Ia and have been developedespecially for the use according to the invention.

Preferred compounds of formula I are those wherein R is bromine or R₁SO₂and R₂ is methyl. The present invention accordingly relates also to thecompounds of formulae I and III.

The present invention accordingly relates also to the use of compoundsof formula I in the preparation of 7-thio-3H-isobenzofuran-1-onederivatives of formula Ia

wherein R₂ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, wherein a compoundof formula I

wherein R is halogen, R₁SO₂ or (R₁)₂NC(X)O; X is O or S; R₁ isC₁-C₈alkyl, aryl-C₁-C₈alkyl, C₁-C₈haloalkyl or aryl; and R₂ is asdefined above, is reacted at elevated reaction temperature in thepresence of sulfur in a nucleophilic aromatic substitution reaction withan alkali metal sulfide, disulfide or polysulfide of formula XM₂S_(q)  (X),wherein M is an alkali metal or hydrogen, and q is 1, 2 or a fractionalnumber from 1 to 7, with the proviso that at least one M is an alkalimetal (halogen-sulfide exchange; Reaction scheme 3), and optionally,when a reagent of formula X wherein q>1 is used, is worked-upreductively and, after the reaction mixture has been rendered acidic,the desired target compound of formula Ia is isolated therefrom andoptionally re-isolated in the form of the salt using a strongly basicaqueous solution.

As alkali metal sulfides or disulfides of formula X for the nucleophilicaromatic substitution reaction (halogen-sulfide exchange) in thecompound of formula I, it is possible to use, for example, sodiumsulfide (Na₂S), potassium sulfide (K₂S), lithium sulfide (Li₂S), sodiumpotassium sulfide (NaKS), sodium disulfide (Na₂S₂), sodium potassiumdisulfide (NaKS₂), and also alkali metal hydrosulfides and alkali metalhydrodisulfides, for example sodium hydrosulfide (NaHS), potassiumhydrosulfide (KHS) and sodium hydrodisulfide (NaHS₂) (Reaction scheme3), the disulfides preferably being prepared in situ in a solvent, suchas e.g. an amide, for example DMF, from elemental sulfur and an alkalimetal sulfide, e.g. sodium sulfide, analogously to the manner described,e.g. in Gazz. Chim. Ital. 110, 301 (1980), J. Am. Chem. Soc. 68, 498(1946) and Chem. Pharm. Bull. 33, 5184 (1985).

The alkali metal sulfides and disulfides of formula X are advantageouslyused in equimolar amounts or in an excess of from 2 to 50 mol %, basedon the compound of formula I.

After adjustment of the pH range of the reaction mixture to the acidrange, preferably to the pH range of from 1 to 5, the desired compoundof formula Ia can be isolated, optionally after reductive working-upwhen q is 2 in the compound of formula X that is used (disulfides), andthen optionally re-isolated from the organic phase using a stronglybasic aqueous solution (Example P6).

Solvents suitable for the nucleophilic aromatic substitution of thecompounds of formula I are generally, for example, alcohols, ethers,aromatic hydrocarbons, sulfoxides, amides, esters or water, or mixturesthereof, for example ethanol, propanol, butanol, 2-methoxyethanol,tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide,N,N-dimethylformamide, 1-methyl-2-pyrrolidone, N,N-dimethylacetamide,ethyl acetate or water, or mixtures thereof.

The nucleophilic aromatic substitution of the compounds of formula I iscarried out at a reaction temperature of from −20° to 160° C.,preferably from 80° to 100° C., and at normal pressure (1 bar) or in asealed system at an elevated pressure of from 1.1 to 100 bar.

Optionally, it is possible additionally to add phase transfer catalysts,especially quaternary ammonium salts, such as e.g. tetraalkylammoniumhalides, for example tetrabutylammonium chloride andtricaprylomethylammonium chloride (aliquat), as solubilisers between thedissolved starting material of formula I and the disulfide, which mayhave been prepared in situ, which has the effect of accelerating thereaction. Further phase transfer catalysts suitable for the abovenucleophilic aromatic substitution reaction are described, for example,in Synthesis 1973, 441-456 and in Angew. Chem., Int. Ed. Engl. 13,170-179 (1974). Such phase transfer catalysts are used in amounts offrom 0.1 to 10 mol %, especially from 0.5 to 5 mol %, based on thecompound of formula Ia.

A further characteristic of the use, according to the invention, ofcompounds of formula I is the purification step for the compounds offormula Ia, which follows the nucleophilic aromatic substitution, whichpurification step offers great advantages for industrial-scale processesbecause complicated separation and purification steps can be avoided andthe outlay in terms of apparatus can be reduced.

For that purpose, the reaction mixture rendered aqueous-organicfollowing the nucleophilic aromatic substitution reaction or obtained inthat form from a phase transfer-catalysed reaction procedure is adjustedto an acidic pH range of from 1 to 5 with aqueous acid, that acidicreaction mixture is optionally worked-up reductively, and the product isextracted with organic solvents, such as e.g. aromatic hydrocarbons, forexample toluene, or ethers, for example THF or dioxane, and the producttaken up in the organic phase is optionally re-isolated with an aqueousstrong base, preferably in the pH range of from 12 to 14, such as e.g.an alkali metal hydroxide. The compound of formula Ia is thus obtainedin the form of a salt in an aqueous solution e.g. as an alkali metal,alkaline earth metal or ammonium salt (Example P6).

Suitable reducing agents for the reductive working-up of resulting di-and poly-sulfides are, for example, diborane, hydrazine and phosphines,which are used in sub-stoichiometric amounts, in equimolar amounts or ina slight excess of from 5 to 15 mol %, based on the compound of formulaI used.

Suitable reducing agents are also borohydrides, which are advantageouslyused in sub-stoichiometric amounts of, for example, from 0.1 to 0.2molar equivalent, based on the compound of formula I used.

The reductive working-up is carried out at reaction temperatures of from0° to 80° C., preferably from 10° to 40° C.

In an especially preferred variant of the use according to the inventionof compounds of formula I, the nucleophilic aromatic substitutionreaction in the compound of formula I is carried out using sodiumdisulfide, prepared in situ from an equimolar mixture of elementalsulfur and sodium sulfide, in 2-methoxyethanol or N,N-dimethylformamide(DMF) as solvent at a reaction temperature of from 80° to 100° C. for 1hour and, after the addition of toluene and water, adjustment of thereaction mixture with acid to a pH range of from 1 to 5, extraction ofthe compound of formula Ia with toluene and then optionallyback-extraction of the compound of formula Ia from the toluene phasewith an aqueous strong base.

As acid for adjusting the reaction mixture to a pH range of from 1 to 5there comes into consideration especially an aqueous solution of amineral acid, such as e.g. sulfuric or hydrochloric acid.

As aqueous strong base for the back-extraction of the compound offormula Ia (in the form of the salt) from the organic phase there comesinto consideration especially an aqueous solution of a hydroxide, suchas e.g. an alkali metal hydroxide, for example sodium hydroxidesolution, with preference being given to the use of a 30% sodiumhydroxide solution.

The desired target compound of formula Ia is then in the form of a saltdissolved in water, which can readily be separated out by concentrationof the water phase.

The yields of isolated product of formula Ia from the halogen-sulfideexchange reaction are generally >90% of theory (depending on the solventused, the amount and ratio of alkali metal sulfide/sulfur, the natureand purity of the halide starting material, the duration of the reactionand the method of working-up) with the final product having a purity of>99%.

The present invention relates also to the use of compounds of formulaIII in the preparation of 7-thio-3H-isobenzofuran-1-one derivatives offormula Ia

wherein R₂ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, wherein a compoundof formula III

wherein R is halogen, R₁S(O)₂ or (R₁)₂NC(X)O; R₁ is C₁-C₈alkyl,aryl-C₁-C₈alkyl, C₁-C₈-haloalkyl or aryl; X is O or S; and R₃ isC₁-C₅alkyl or C₁-C₅haloalkyl, is subjected to benzylic lactonisation inthe ortho-position alkyl chain R₃ in the presence of a free-radicalinitiator and a halogenating agent, yielding a compound of formula I

wherein R and R₂ are as defined above, which compound is then reacted atelevated reaction temperature in the presence of sulfur in anucleophilic aromatic substitution reaction with an alkali metalsulfide, disulfide or polysulfide of formula XM₂S_(q)  (X),wherein M is an alkali metal or hydrogen, and q is 1, 2 or a fractionalnumber from 1 to 7, with the proviso that at least one M is an alkalimetal (halogen-sulfide exchange), and optionally, when a reagent offormula X wherein q>1 is used, is worked up reductively and, after thereaction mixture has been rendered acidic, the desired target compoundof formula Ia is isolated therefrom and optionally re-isolated in theform of the salt using a strongly basic aqueous solution.

For the use of compounds of formula III in the preparation of compoundsof formula Ia, the preferred meanings are the same as those alreadygiven above.

The process according to the invention differs from known processes inthat:

1) reduction of a nitro compound is not necessary and therefore there isno formation of hydroxylamine, which would adversely affect the thermalsafety,

2) there is no reaction with butyllithium, which is expensive andunfavourable for process safety, as described, e.g. in Monatsh. Chem.123(12), 1125 (1992),

3) the number of toxic starting compounds and reagents is reduced (onlyCO in Step (2) and the halogenating reagents in Step (3) are toxic),

4) readily accessible and inexpensive starting compounds are used,

5) the lactonisation is achieved in a single step and in high yields,

6) the reaction sequence to obtain the desired target compound offormula I is reduced by one reaction step,

7) in respect of Steps (1) and (2) (diazotisation and carbonylation),the reaction can be designed as a one-pot reaction,

8) the method of working-up is simple and effective,

9) the number of volatile, unpleasant-smelling, toxic waste products isreduced, and

10) the overall yields are higher, simultaneously combined with a highdegree of product purity, e.g. in respect of the target compound offormula Ia.

The advantages of the present process compared with known processes areaccordingly:

1) its particular suitability for industrial-scale applications with asubstantially better waste outcome, e.g. in respect of volatile,sulfur-containing byproducts when using xanthogenates, as in e.g. Pest.Manag Sci. 57, 205-224 (2001), and the small amount of disulfidesformed,

2) the high thermal safety of the process,

3) the great variety in its reaction media and reaction conditions,

4) its avoidance of complicated separation and purification steps,

5) the possibility of using the formed diazonium salt of formula IIfurther directly in a one-pot process without changing the solvent, thusreducing solvent wastes and the outlay in terms of apparatus,

6) the high volumetric concentration of the reactants,

7) its high product yields and product purities,

8) its large number of suitable palladium catalysts,

9) its use of catalysts that are either commercially available or can beprepared readily in situ from commercial palladium salts, such as e.g.palladium(II) chloride solution (20%), and the appropriate ligands, and

10) its reproducibility.

The 7-thio-3H-isobenzofuran-1-one derivatives prepared according to theinvention are used especially as intermediates in the preparation of7-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methyl-3H-isobenzofuran-1-oneby reacting 7-thio-3-methyl-3H-isobenzofuran-1-one of formula Ia

wherein R₂ is methyl, advantageously in an inert organic solvent, suchas e.g. an ether, ketone, nitrile or amide, for example tetrahydrofuran,butanone, acetonitrile or N,N-dimethylformamide (DMF), at temperaturesof from 0 to 160° C., with a compound of formula VI

as described, for example, in EP-B-0 447 506.

The following Examples illustrate the process according to the inventionfurther.

EXAMPLE P1 Preparation of 2-chloro-6-ethyl-benzoic acid

3.60 g (21.2 mmol) of 2-chloro-6-ethylaniline and 2.70 g (26.5 mmol) ofsulfuric acid (96%) in 100 ml of acetic acid are introduced into areaction vessel and the clear, colourless solution is cooled to 10° C.At that temperature, a solution of 1.46 g (21.2 mmol) of sodium nitritein 8 ml of water is slowly added in the course of 15 minutes. When adiazo colour test, e.g. using dimethylaniline-coated indicator paper, ispositive and a colour spot test, e.g. using KI indicator paper moistenedwith 1N aqueous hydrochloric acid solution, is negative, the reactionmixture is transferred to a glass autoclave and rinsed with 20 ml ofacetic acid. The autoclave is flushed out three times with nitrogen at atemperature of 10° C. and then flushed out three times with CO at 7° C.55 mg of Pd₂(dba)₃.CHCl₃ (0.053 mmol) in 2 ml of acetic acid are thenmetered in using a cannula, a CO pressure of 6.3 bar is applied and thereaction mixture is stirred overnight at 20° C.

After the pressure has been released, 25 ml of a 1N aqueous sodiumhydroxide solution are added and the resulting suspension is filtered.The orange-brown filtrate is adjusted to pH 2 with sulfuric acid andextracted three times with 40 ml of toluene each time. The combinedorganic phases are washed three times with 40 ml of water each time,dried over sodium sulfate and concentrated by evaporation under reducedpressure using a rotary evaporator. The crude yield is 3.24 g with atarget compound content of 70% according to HPLC. The pure yield of thedesired target compound after purification by means of vacuumdistillation (b.p. 130-135° C./0.01 mbar) is 2.24 g (57% of theory).

EXAMPLE P2 Preparation of 2-chloro-6-ethyl-benzoic acid

3.60 g (21.2 mmol) of 2-chloro-6-ethylaniline in 60 ml of acetic acid isintroduced into a reaction vessel and the clear, colourless solution iscooled to 6° C. At that temperature, 3.64 g (22.7 mmol) of a 43% aqueoussodium nitrite solution are added and then, in the course of 15 minutes,a solution of 4.32 g (42.4 mmol) of sulfuric acid (96%) in 7 ml ofacetic acid is added dropwise. The resulting dark-red solution is thenstirred for 30 minutes. When a diazo colour test, for example usingdimethylaniline-coated indicator paper, is positive and a colour spottest, e.g. using KI indicator paper moistened with aqueous 1Nhydrochloric acid solution, is negative, 15 mg of sulfamic acid areadded and then, at a temperature of 10° C., 8.7 ml (91.6 mmol) of aceticanhydride are added. The reaction mixture is then transferred to a glassautoclave and rinsed with 20 ml of acetic acid. At a temperature of 20°C. the autoclave is flushed out three times with nitrogen and thenflushed out three times with CO. 220 mg of Pd₂(dba)₃.CHCl₃ (0.212 mmol)in 5 ml of acetic acid are then metered in using a cannula at a COpressure of 1 bar, then a CO pressure of 8 bar is applied and thereaction mixture is stirred overnight at 45° C. When the pressure hasbeen released, the resulting suspension is filtered and the acetic acidfiltrate is concentrated by evaporation under reduced pressure using arotary evaporator; 1M aqueous hydrochloric acid solution is added to theorganic phase that remains and extraction is carried out three timeswith toluene. The combined organic phases are evaporated under reducedpressure using a rotary evaporator, yielding 4.43 g of crude productwith a target compound content of 75% according to HPLC. Purification bymeans of vacuum distillation (b.p. 130-135° C./0.01 mbar) yields 3.31 g(yield 85% of theory) of the desired target compound.

EXAMPLE P3 Preparation of 2-chloro-6-ethyl-benzoic acid

3.60 g (21.2 mmol) of 2-chloro-6-ethylaniline in 24 ml of acetic acidare introduced into a reaction vessel and the clear, colourless solutionis cooled to 11° C. At that temperature, 3.25 g (31.8 mmol) of sulfuricacid (96%) are added and then, in the course of 15 minutes, 3.64 g (22.7mmol) of a 43% aqueous sodium nitrite solution are added. The resultingdark-red solution is then stirred for 30 minutes. When a diazo colourtest, e.g. using dimethylaniline-coated indicator paper, is positive anda colour spot test, e.g. using KI indicator paper moistened with aqueous1N hydrochloric acid solution, is negative, 15 mg of sulfamic acid areadded and then, at a temperature of 10° C., 8.7 ml (91.6 mmol) of aceticanhydride are added. The reaction mixture is then transferred to a glassautoclave and rinsed with 6 ml of acetic acid. At a temperature of 20°C. the autoclave is flushed out three times with nitrogen and then threetimes with CO. 220 mg of Pd₂(dba)₃.CHCl₃ (0.212 mmol) in 3 ml of aceticacid are metered in using a cannula at a CO pressure of 1 bar, then a COpressure of 8 bar is applied and the reaction mixture is stirred for 5hours at 45° C.

When the pressure has been released, the resulting suspension isfiltered and the acetic acid filtrate is concentrated by evaporationunder reduced pressure using a rotary evaporator; 1M aqueoushydrochloric acid solution is added to the organic phase that remainsand extraction is carried out three times with toluene. The combinedorganic phases are evaporated under reduced pressure using a rotaryevaporator, yielding 3.72 g of crude product with a target compoundcontent of 75% according to HPLC. Purification by means of vacuumdistillation (b.p. 130-135° C./0.01 mbar) yields 2.12 g (yield 55% oftheory) of the desired target compound.

EXAMPLE P4 Preparation of 7-chloro-3-methyl-3H-isobenzofuran-1-one

5.00 g (0.027 mol) of 2-chloro-6-ethylbenzoic acid in 120 ml ofchlorobenzene are introduced into a reaction vessel and heated to 90° C.0.1 g of α,α′-azoisobutyronitrile is then added, followed by 5.04 g(0.03154 mol) of bromine in 25 ml of chlorobenzene, which is metered inthe course of 10 minutes. The reaction mixture is then stirred for 1hour at 90° C. to complete the reaction. After the reaction mixture hascooled to 20° C., it is washed with 50 ml of sodium thiosulfate solution(0.1 mol), the organic phase is dried over sodium sulfate and thesolvent evaporated off under reduced pressure using a rotary evaporator.The desired target compound is obtained in a yield of 6.1 g and a purityof about 74% (corresponding to 90% of theory).

EXAMPLE P5 Preparation of 7-thio-3-methyl-3H-isobenzofuran-1-one

5.70 g of 7-chloro-3-methyl-3H-isobenzofuran-1-one is introduced into areaction vessel together with 1.30 g of sulfur and 5.40 g of sodiumsulfide in 30 ml of DMF, the mixture is heated to 90° C. and left toreact for 1 hour. Once all the starting material has reacted, thereaction mixture is cooled to 20° C., 50 ml of toluene and 30 ml ofwater are added and the mixture is adjusted to a pH of 3. The resultingsuspension is filtered over Hyflo and the organic phase is separatedfrom the two-phase mother liquor. The organic phase is then extractedwith 50 ml of aqueous sodium hydroxide solution. The desired targetcompound is obtained in the form of the sodium salt in a yield of 4.3 g(80% of theory).

EXAMPLE P6 Preparation of 7-thio-3-methyl-3H-isobenzofuran-1-one

15 g of 2-methoxyethanol are introduced into a 200 ml reaction vesseland, together with 1.9 g of 7-chloro-3-methyl-3H-isobenzofuran-1-one,1.8 g of sodium sulfide and 0.43 g of sulfur, are heated to 110° C.After 6 hours' reaction time, the mixture is cooled to 20° C. and amixture of 20 ml of water and 1 ml of 12% sodium borohydride solution isadded. After being left to stand for 5 minutes, 20 ml of toluene areadded and the pH value of the reaction mixture is adjusted to from 1 to1.5 with hydrochloric acid. The organic phase is separated off and thenextraction is carried out twice with 10 ml of aqueous sodium hydroxidesolution. The desired target compound is obtained in the form of thesodium salt in a yield of 80% as a 2.8% aqueous solution.

EXAMPLE P7 Preparation of 7-thio-3-methyl-3H-isobenzofuran-1-one

The reaction is started analogously to the manner described above inExample P5. Working-up of the desired target compound is carried outreductively by means of extraction from an acid medium, separation ofthe organic phase and treatment thereof with 5 mol % triphenylphosphine.Back-extraction of the reaction mixture with 25 ml of sodium hydroxidesolution yields the desired target compound in the form of the sodiumsalt in an aqueous solution in a yield of 82%.

1. A compound of formula I

wherein R is fluorine, bromine, iodine, R₁S(O)_(n) or (R₁)₂NC(X)O; R₁ isC₁-C₈alkyl, C₁-C₈-haloalkyl, aryl-C₁-C₈alkyl or aryl; n is 0, 1, 2 or 3;X is O or S; and R₂ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, with theproviso that R₁ is different from C₁-C₈ alkyl or aryl if X is S, R isdifferent from iodine if R₂ is methyl, and R is different from fluorine,bromine or iodine if R₂ is hydrogen.
 2. The compound according to claim1, wherein R is bromine and R₂ is methyl
 3. The compound according toclaim 1 wherein R is R₁SO₂; R₁ is C₁-C₈alkyl, C₁-C₈-haloalkyl,aryl-C₁-C₈alkyl or aryl; and R₂ is methyl.